Longevity genes are of obvious interest and importance, both for their life-extension potential and the possibility of their contributing to the enhancement of the quality of life. However, very few of these genes have been identified and even less is understood about how these genes act to prevent aging and promote life extension. Accordingly, there exists the need to discover genes whose function is associated with life-extension. These genes and their products would be useful in the screening for anti-aging agents and would serve as key targets in various anti-aging therapies. Ultimately, such tools could help to alleviate cognitive and motor function deficits in the aged population and thereby prolong the independence of the elderly.
The roundworm C. elegans has proved a valuable invertebrate model system to study aging owing to its short, reproducible life span and its amenability to genetic and molecular analysis. In molecular genetics, extended life span is one of the best indicators that an intervention in an aging process has been made, and the isolation of long-lived variants in C. elegans has provided important insights into the mechanisms of aging in the central nervous system. As the entire C. elegans genome is sequenced, it is feasible to envisage in the near future a comprehensive identification of all the genes that affect aging in this organism.
In C. elegans, the main pathway regulating life span is an insulin-like signaling pathway (Apfeld J. & Kenyon C. (1998) Cell 95: 199-210). The daf-2 gene encodes an insulin/IGF-like receptor and is a key molecule that regulates longevity. Mutations in daf-2 or other known signaling molecules in this pathway result in extended life span. The lifespan extension caused by mutations in daf-2 could be rescued when the daf-2 pathway signaling was restored specifically to neurons (C. A. Wolkow et al., (2000) Science 290 (5489):147-150). While the detailed mechanism of insulin signaling and its function in regulating longevity is becoming understood, additional players that regulate longevity remain to be identified. Genetic mosaic analysis of DAF-2 showed that daf-2 (−) cells display a phenotype of daf-2 (+). This result indicates that DAF-2 functions non-autonomously in the regulation of life span and suggests that additional pathways may regulate aging upstream of DAF-2 and the insulin signaling pathway. Indeed, signals from the germ line, mitochondria and sensory neurons in the head of the worm have been shown to regulate life span (S. Hekimi and L. Guarente (2003) Science, 299 (5611):1351-1354). The identification of new signaling pathways involved in regulating longevity could provide critical new targets for insulin regulators in higher organisms and potential anti-aging and Diabetes II targets for drug intervention in humans.